Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor

J Clin Invest. 1999 Nov;104(9):1213-21. doi: 10.1172/JCI7750.


Tissue factor (TF), the cell-surface receptor for coagulation factor VIIa, supports metastasis. Equally important for this process are (a) interactions of the TF cytoplasmic domain, which binds the mobility-enhancing actin-binding protein 280, and (b) the formation of a proteolytically active TF-VIIa complex on the tumor cell surface. In primary bladder carcinoma cells, we find that this complex localizes to the invasive edge, in proximity to tumor-infiltrating vessels that stain intensely for TF pathway inhibitor (TFPI-1), the major inhibitor of the protease activity of the complex. In culture, binding of VIIa to TF-expressing tumor cells is sufficient to allow cell adhesion, migration, and intracellular signaling on immobilized TFPI-1. Immobilized heparin, a mimic for extracellular matrix-associated proteoglycans, binds physiological concentrations of TFPI-1 in a conformation that supports TF-VIIa-dependent cell adhesion. Consistent with a functional role of TFPI-1 in complex extracellular matrices, we show that TF cooperates with integrin-mediated adhesion and migration on composite matrices that contain ligands for both integrins and the TF-VIIa complex. This study thus provides evidence for a novel mechanism of protease-supported migration that is independent of proteolytic matrix degradation but rather involves protease-dependent bridging of TF's extracellular domain to an ECM-associated inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Cell Adhesion
  • Cell Movement
  • Cysteine Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Endopeptidases / metabolism
  • Epithelium / metabolism
  • Epithelium / pathology
  • Factor VIIa / metabolism
  • Fibronectins / pharmacology
  • Glycoproteins / metabolism
  • Heparin / pharmacology
  • Humans
  • Immunohistochemistry
  • Lipoproteins / metabolism
  • Lipoproteins / pharmacology
  • Neoplasm Proteins*
  • Pregnancy Proteins / metabolism
  • Signal Transduction
  • Thromboplastin / metabolism*
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology


  • Fibronectins
  • Glycoproteins
  • Lipoproteins
  • Neoplasm Proteins
  • Pregnancy Proteins
  • lipoprotein-associated coagulation inhibitor
  • tissue-factor-pathway inhibitor 2
  • Heparin
  • Thromboplastin
  • Endopeptidases
  • Factor VIIa
  • Cysteine Endopeptidases
  • cancer procoagulant